Testing For Glucose-6-phosphate Dehydrogenase Deficiency Research Articles

Point-of-Care Testing for G6PD Deficiency: Opportunities for Screening.

Glucose-6-phosphate dehydrogenase (G6PD) deficiency, an X-linked genetic disorder, is associated with increased risk of jaundice and kernicterus at birth. G6PD deficiency can manifest later in life as severe hemolysis, when the individual is exposed to oxidative agents that range from foods such as fava beans, to diseases such as typhoid, to medications such as dapsone, to the curative drugs for Plasmodium (P.) vivax malaria, primaquine and tafenoquine. While routine testing at birth for G6PD deficiency is recommended by the World Health Organization for populations with greater than 5% prevalence of G6PD deficiency and to inform P. vivax case management using primaquine, testing coverage is extremely low. Test coverage is low due to the need to prioritize newborn interventions and the complexity of currently available G6PD tests, especially those used to inform malaria case management. More affordable, accurate, point-of-care (POC) tests for G6PD deficiency are emerging that create an opportunity to extend testing to populations that do not have access to high throughput screening services. Some of these tests are quantitative, which provides an opportunity to address the gender disparity created by the currently available POC qualitative tests that misclassify females with intermediate G6PD activity as normal. In populations where the epidemiology for G6PD deficiency and P. vivax overlap, screening for G6PD deficiency at birth to inform care of the newborn can also be used to inform malaria case management over their lifetime.

Use of primaquine and glucose-6-phosphate dehydrogenase deficiency testing: Divergent policies and practices in malaria endemic countries.

Primaquine is the only available antimalarial drug that kills dormant liver stages of Plasmodium vivax and Plasmodium ovale malarias and therefore prevents their relapse (‘radical cure’). It is also the only generally available antimalarial that rapidly sterilises mature P. falciparum gametocytes. Radical cure requires extended courses of primaquine (usually 14 days; total dose 3.5–7 mg/kg), whereas transmissibility reduction in falciparum malaria requires a single dose (formerly 0.75 mg/kg, now a single low dose [SLD] of 0.25 mg/kg is recommended). The main adverse effect of primaquine is dose-dependent haemolysis in glucose 6-phosphate dehydrogenase (G6PD) deficiency, the most common human enzymopathy. X-linked mutations conferring varying degrees of G6PD deficiency are prevalent throughout malaria-endemic regions. Phenotypic screening tests usually detect <30% of normal G6PD activity, identifying nearly all male hemizygotes and female homozygotes and some heterozygotes. Unfortunately, G6PD deficiency screening is usually unavailable at point of care, and, as a consequence, radical cure is greatly underused. Both haemolytic risk (determined by the prevalence and severity of G6PD deficiency polymorphisms) and relapse rates vary, so there has been considerable uncertainty in both policies and practices related to G6PD deficiency testing and use of primaquine for radical cure. Review of available information on the prevalence and severity of G6PD variants together with countries’ policies for the use of primaquine and G6PD deficiency testing confirms a wide range of practices. There remains lack of consensus on the requirement for G6PD deficiency testing before prescribing primaquine radical cure regimens. Despite substantially lower haemolytic risks, implementation of SLD primaquine as a P. falciparum gametocytocide also varies. In Africa, a few countries have recently adopted SLD primaquine, yet many with areas of low seasonal transmission do not use primaquine as an antimalarial at all. Most countries that recommended the higher 0.75 mg/kg single primaquine dose for falciparum malaria (e.g., most countries in the Americas) have not changed their recommendation. Some vivax malaria–endemic countries where G6PD deficiency testing is generally unavailable have adopted the once-weekly radical cure regimen (0.75 mg/kg/week for 8 weeks), known to be safer in less severe G6PD deficiency variants. There is substantial room for improvement in radical cure policies and practices.

Diagnostic performances of the fluorescent spot test for G6PD deficiency in newborns along the Thailand-Myanmar border: A cohort study

Background: Glucose-6-phosphate dehydrogenase (G6PD) deficiency is an inherited enzymatic disorder associated with severe neonatal hyperbilirubinemia and acute haemolysis after exposure to certain drugs or infections. The disorder can be diagnosed phenotypically with a fluorescent spot test (FST), which is a simple test that requires training and basic laboratory equipment. This study aimed to assess the diagnostic performances of the FST used on umbilical cord blood by locally-trained staff and to compare test results of the neonates at birth with the results after one month of age. Methods: We conducted a cohort study on newborns at the Shoklo Malaria Research Unit, along the Thai-Myanmar border between January 2015 and May 2016. The FST was performed at birth on the umbilical cord blood by locally-trained staff and quality controlled by specialised technicians at the central laboratory. The FST was repeated after one month of age. Genotyping for common local G6PD mutations was carried out for all discrepant results. Results: FST was performed on 1521 umbilical cord blood samples. Quality control and genotyping revealed 10 misdiagnoses. After quality control, 10.7% of the males (84/786) and 1.2% of the females (9/735) were phenotypically G6PD deficient at birth. The FST repeated at one month of age or later diagnosed 8 additional G6PD deficient infants who were phenotypically normal at birth. Conclusions: This study shows the short-comings of the G6PD FST in neonatal routine screening and highlights the importance of training and quality control. A more conservative interpretation of the FST in male newborns could increase the diagnostic performances. Quantitative point-of-care tests might show higher sensitivity and specificity for diagnosis of G6PD deficiency on umbilical cord blood and should be investigated.

Evaluation of a Novel Quantitative Test for Glucose-6-Phosphate Dehydrogenase Deficiency: Bringing Quantitative Testing for Glucose-6-Phosphate Dehydrogenase Deficiency Closer to the Patient

.Glucose-6-phosphate dehydrogenase (G6PD) deficiency, a common genetic blood condition, can result in kernicterus at birth, and later in life as severe hemolysis on exposure to certain infections, foods, and drugs. The unavailability of point-of-care tests for G6PD deficiency is a barrier to routine curative treatment of Plasmodium vivax malaria with 8-aminoquinolines, such as primaquine. Two quantitative reference tests (Trinity Biotech, Bray, Ireland and Pointe Scientific, Canton, MI; Cat No. G7583) and the point-of-care STANDARD™ G6PD test (SD Biosensor, Suwon, South Korea) were evaluated. The STANDARD G6PD test was evaluated at multiple temperatures, in anticoagulated venous and capillary samples, including 79 G6PD-deficient and 66 intermediate samples and across two laboratories, one in the United States and one in Thailand. The STANDARD test performed equivalently to a reference assay for its ability to diagnose G6PD deficiency (< 30% normal) with a sensitivity of 100% (0.95 confidence interval [CI]: 95.7–100) and specificity of 97% (0.95 CI: 94.5–98.5), and could reliably identify females with less than 70% normal G6PD activity with a sensitivity of 95.5% (0.95 CI: 89.7–98.5) and specificity of 97% (0.95 CI: 94.5–98.6). The STANDARD G6PD product represents an opportunity to diagnose G6PD deficiency equally for males and females in basic clinical laboratories in high- and low-resource settings. This quantitative point-of-care diagnostic test for G6PD deficiency can provide equal access to safe radical cure of P. vivax cases in high- and low-resource settings, for males and females and may support malaria elimination, in countries where P. vivax is endemic.

Diagnostic performances of the fluorescent spot test for G6PD deficiency in newborns along the Thailand-Myanmar border: A cohort study.

Background: Glucose-6-phosphate dehydrogenase (G6PD) deficiency is an inherited enzymatic disorder associated with severe neonatal hyperbilirubinemia and acute haemolysis after exposure to certain drugs or infections. The disorder can be diagnosed phenotypically with a fluorescent spot test (FST), which is a simple test that requires training and basic laboratory equipment. This study aimed to assess the diagnostic performances of the FST used on umbilical cord blood by locally-trained staff and to compare test results of the neonates at birth with the results after one month of age. Methods: We conducted a cohort study on newborns at the Shoklo Malaria Research Unit, along the Thai-Myanmar border between January 2015 and May 2016. The FST was performed at birth on the umbilical cord blood by locally-trained staff and quality controlled by specialised technicians at the central laboratory. The FST was repeated after one month of age. Genotyping for common local G6PD mutations was carried out for all discrepant results. Results: FST was performed on 1521 umbilical cord blood samples. Quality control and genotyping revealed 10 misdiagnoses. After quality control, 10.7% of the males (84/786) and 1.2% of the females (9/735) were phenotypically G6PD deficient at birth. The FST repeated at one month of age or later diagnosed 8 additional G6PD deficient infants who were phenotypically normal at birth. Conclusions: This study shows the short-comings of the G6PD FST in neonatal routine screening and highlights the importance of training and quality control. A more conservative interpretation of the FST in male newborns could increase the diagnostic performances. Quantitative point-of-care tests might show higher sensitivity and specificity for diagnosis of G6PD deficiency on umbilical cord blood and should be investigated.

Recombinant human G6PD for quality control and quality assurance of novel point-of-care diagnostics for G6PD deficiency.

BackgroundA large gap for the support of point-of-care testing is the availability of reagents to support quality control (QC) of diagnostic assays along the supply chain from the manufacturer to the end user. While reagents and systems exist to support QC of laboratory screening tests for glucose-6-phosphate dehydrogenase (G6PD) deficiency, they are not configured appropriately to support point-of-care testing. The feasibility of using lyophilized recombinant human G6PD as a QC reagent in novel point-of-care tests for G6PD deficiency is demonstrated.MethodsHuman recombinant G6PD (r-G6PD) was expressed in Escherichia coli and purified. Aliquots were stored at -80°C. Prior to lyophilization, aliquots were thawed, and three concentrations of r-G6PD (representing normal, intermediate, and deficient clinical G6PD levels) were prepared and mixed with a protective formulation, which protects the enzyme activity against degradation from denaturation during the lyophilization process. Following lyophilization, individual single-use tubes of lyophilized r-G6PD were placed in individual packs with desiccants and stored at five temperatures for one year. An enzyme assay for G6PD activity was used to ascertain the stability of r-G6PD activity while stored at different temperatures.ResultsLyophilized r-G6PD is stable and can be used as a control indicator. Results presented here show that G6PD activity is stable for at least 365 days when stored at -80°C, 4°C, 30°C, and 45°C. When stored at 55°C, enzyme activity was found to be stable only through day 28.ConclusionsLyophilized r-G6PD enzyme is stable and can be used as a control for point-of-care tests for G6PD deficiency.

Rapid diagnostic test for G6PD deficiency in Plasmodium vivax-infected men: a budget impact analysis based in Brazilian Amazon.

The aim of this study was to estimate the incremental budget impact (IBI) of a rapid diagnostic test to detect G6PDd in male patients infected with Plasmodium vivax in the Brazilian Amazon, as compared with the routine protocol recommended in Brazil which does not include G6PDd testing. The budget impact analysis was performed from the perspective of the Brazilian health system, in the Brazilian Amazon for the years 2013, 2014 and 2015. The analysis used a decision model to compare two scenarios: the first consisting of the routine recommended in Brazil which does not include prior diagnosis of dG6PD, and the second based on the use of RDT CareStart™ G6PD (CS-G6PD) in all male subjects diagnosed with vivax malaria. The expected implementation of the diagnostic test was 30% in the first year, 70% the second year and 100% in the third year. The analysis identified negative IBIs which were progressively smaller in the 3 years evaluated. The sensitivity analysis showed that the uncertainties associated with the analytical model did not significantly affect the results. A strategy based on the use of CS-G6PD would result in better use of public resources in the Brazilian Amazon.

Mass primaquine treatment to eliminate vivax malaria: lessons from the past.

Recent successes in malaria control have put malaria eradication back on the public health agenda. A significant obstacle to malaria elimination in Asia is the large burden of Plasmodium vivax, which is more difficult to eliminate than Plasmodium falciparum. Persistent P. vivax liver stages can be eliminated only by radical treatment with a ≥ seven-day course of an 8-aminoquinoline, with the attendant risk of acute haemolytic anaemia in individuals with glucose-6-phosphate dehydrogenase (G6PD) deficiency. Primaquine is the only generally available 8-aminoquinoline. Testing for G6PD deficiency is not widely available, and so whilst it is widely recommended, primaquine is often not prescribed. In the past, some countries aiming for vivax malaria eradication deployed mass treatments with primaquine on a massive scale, without G6PD testing. In Azerbaijan, Tajikistan (formerly USSR), North Afghanistan and DPR Korea 8,270,185 people received either a 14-day “standard” or a 17-day “interrupted” primaquine treatment to control post-eradication malaria epidemics. These mass primaquine preventive treatment campaigns were conducted by dedicated teams who administered the drugs under supervision and then monitored the population for adverse events. Despite estimated G6PD prevalences up to 38.7%, the reported frequency of severe adverse events related to primaquine was very low. This experience shows that with careful planning and implementation of mass treatment strategies using primaquine and adequate medical support to manage haemolytic toxicity, it is possible to achieve high population coverage, substantially reduce malaria transmission, and manage the risk of severe acute haemolytic anaemia in communities with a relatively high prevalence of G6PD deficiency safely.

Single-dose radical cure of Plasmodium vivax: a step closer

Single-dose radical cure of Plasmodium vivax: a step closer

G6PD testing in support of treatment and elimination of malaria: recommendations for evaluation of G6PD tests

Malaria elimination will be possible only with serious attempts to address asymptomatic infection and chronic infection by both Plasmodium falciparum and Plasmodium vivax. Currently available drugs that can completely clear a human of P. vivax (known as “radical cure”), and that can reduce transmission of malaria parasites, are those in the 8-aminoquinoline drug family, such as primaquine. Unfortunately, people with glucose-6-phosphate dehydrogenase (G6PD) deficiency risk having severe adverse reactions if exposed to these drugs at certain doses. G6PD deficiency is the most common human enzyme defect, affecting approximately 400 million people worldwide.Scaling up radical cure regimens will require testing for G6PD deficiency, at two levels: 1) the individual level to ensure safe case management, and 2) the population level to understand the risk in the local population to guide Plasmodium vivax treatment policy. Several technical and operational knowledge gaps must be addressed to expand access to G6PD deficiency testing and to ensure that a patient’s G6PD status is known before deciding to administer an 8-aminoquinoline-based drug.In this report from a stakeholder meeting held in Thailand on October 4 and 5, 2012, G6PD testing in support of radical cure is discussed in detail. The focus is on challenges to the development and evaluation of G6PD diagnostic tests, and on challenges related to the operational aspects of implementing G6PD testing in support of radical cure. The report also describes recommendations for evaluation of diagnostic tests for G6PD deficiency in support of radical cure.

Prevalence and molecular basis of glucose-6-phosphate dehydrogenase deficiency in Afghan populations: implications for treatment policy in the region

BackgroundGlucose-6-phosphate dehydrogenase deficiency (G6PD), an x-linked inherited enzymopathy, is a barrier to malaria control because primaquine cannot be readily applied for radical cure in individuals with the condition. In endemic areas, including in Afghanistan, the G6PD status of vivax patients is not routinely determined so the drug is rarely, if ever, prescribed even though it is included as a recommended treatment in local, regional and global guidelines. This study assessed the prevalence and genotype of G6PD deficiency in Afghan populations and examined the need for routine G6PD testing as a malaria treatment and control tool.MethodsA cross-sectional household survey was conducted using random sampling in five Afghan cities to determine the prevalence of G6PD deficiency in Afghan ethnic groups. Filter-paper blood spots were analysed for phenotypic G6PD deficiency using a fluorescent spot test. Molecular analysis was conducted to identify the genetic basis of the disorder.ResultsOverall, 45/1,436 (3.1%) people were G6PD deficient, 36/728 (5.0%) amongst males and 9/708 (1.3%) amongst females. Amongst males the prevalence was highest in the Pashtun ethnic group (10%, 26/260) while in Tajik males it was 8/250 (3.2%); in Hazara males it was 1/77 (1.3%) and in Uzbek males is was 0/125. Genetic testing in those with deficiency showed that all were of the Mediterranean type (Med-) characterized by a C-T change at codon 563 of the G6PD gene.ConclusionPrevalence of G6PD deficiency in Afghanistan varies considerably by ethnic group and is predominantly of the Mediterranean type. G6PD deficient individuals are susceptible to potentially severe and life-threatening haemolysis after standard primaquine treatment. If the aim of increasing access to radical treatment of vivax is to be successful reliable G6PD testing needs to be made routinely available within the health system.

Should we screen newborns for glucose-6-phosphate dehydrogenase deficiency in the United States?

Glucose-6-phosphate dehydrogenase (G6PD) deficiency, a common X-linked enzymopathy can lead to severe hyperbilirubinemia, acute bilirubin encephalopathy and kernicterus in the United States. Neonatal testing for G6PD deficiency is not yet routine and the American Academy of Pediatrics recommends testing only in jaundiced newborns who are receiving phototherapy whose family history, ethnicity, or geographic origin suggest risk for the condition, or for infants whose response to phototherapy is poor. Screening tests for G6PD deficiency are available, are suitable for use in newborns and have been used in birth hospitals. However, US birth hospitals experience is limited and no national consensus has emerged regarding the need for newborn G6PD testing, its effectiveness or the best approach. Our review of current state of G6PD deficiency screening highlights research gaps and informs specific operational challenges to implement universal newborn G6PD testing concurrent to bilirubin screening in the United States.

Editorial Commentary: Single-Dose Primaquine as Gametocytocidal Treatment in Patients With Uncomplicated Falciparum Malaria

Editorial Commentary: Single-Dose Primaquine as Gametocytocidal Treatment in Patients With Uncomplicated Falciparum Malaria

Increased morbidity in acute viral hepatitis with glucose-6-phosphate dehydrogenase deficiency

Editor, Viral hepatitis usually manifests as a self-limiting illness. However, in the presence of glucose-6-phosphate dehydrogenase (G6PD) deficiency, it may be complicated with renal failure, hemolysis, hepatic encephalopathy and even death. The incidence of G6PD deficiency in the general population in northern India ranges from 2.2 % to 14 % [1]. We retrospectively analyzed the clinical presentation and outcome of patients with G6PD deficiency and acute viral hepatitis. The case records of all patients admitted in our hospital with acute viral hepatitis between January 2007 and December 2010 and ten patients (mean age 16.1 years, M:F 4:1) with G6PD deficiency and acute viral hepatitis were identified. Fourteen patients (mean age 19.3 years, M:F 5:2) with acute viral hepatitis and without G6PD deficiency were randomly selected by draw of lots for comparison. Both the groups were analyzed on the basis of age, sex, etiology of hepatitis, peak bilirubin levels, peak creatinine levels, prothrombin time, requirement of hemodialysis, hospital stay and outcome. Seven patients in the study group had hepatitis A infection and three had hepatitis E infection. In the control group, eight patients had hepatitis A, five had hepatitis E and one had mixed hepatitis A and E infection. As noted from Table 1, the mean peak bilirubin was significantly higher in the study group (p<0.001). Peak creatinine value was not significantly increased when compared to the control group. The mean international normalized ratio and indirect bilirubin was significantly higher in the study group. The mean duration of stay was nearly two and a half times more in the study group than in the control group. Mild hemolysis is seen in acute viral hepatitis but is rarely of clinical significance [2]. When viral hepatitis occurs in G6PD deficient individuals, hemolysis may be severe [3]. Gotsman et al. reported a more severe initial presentation in patients with acute viral hepatitis A and G6PD deficiency though the clinical outcome was not affected [4]. Abid and Khan reported five patients with acute viral hepatitis E, severe intravascular hemolysis, hyperbilirubinemia and anemia. Two patients required hemodialysis and they advocated that measures to prevent renal failure should be taken in such patients [5]. Hemolysis may result from decreased levels of reduced glutathione in red blood cells [2], consequent to the accumulation of oxidants due to hepatic dysfunction. Renal tubular dysfunction occurs due to excess hematin and bilirubin which result in obstruction of renal tubules. Good hydration and avoiding nephrotoxic drugs helps in preventing renal failure. Tests for G6PD deficiency may be negative during the hemolytic phase and should be repeated after 8–10 weeks of recovery. Vitamin K should be avoided in these patients. Studies from various parts of India have recommended vaccination against hepatitis A and B in communities with high prevalence of G6PD deficiency [6, 7].

Modification to reporting of qualitative fluorescent spot test results improves detection of glucose‐6‐phosphate dehydrogenase (G6PD)‐deficient heterozygote female newborns

The glucose-6-phosphate dehydrogenase (G6PD) fluorescent spot test (FST) is a useful screening test for G6PD deficiency, but is unable to detect heterozygote G6PD-deficient females. We sought to identify whether reporting intermediate fluorescence in addition to absent and bright fluorescence on FST would improve identification of mildly deficient female heterozygotes. A total of 1266 cord blood samples (705 male, 561 female) were screened for G6PD deficiency using FST (in-house method) and a quantitative enzyme assay. Fluorescence intensity of the FST was graded as either absent, intermediate or normal. Samples identified as showing absent or intermediate fluorescence on FST were analysed for the presence of G6PD mutations using TaqMan@SNP genotyping assays and direct nucleotide sequencing. Of the 1266 samples, 87 samples were found to be intermediate or deficient by FST (49 deficient, 38 intermediate). Of the 49 deficient samples, 48 had G6PD enzyme activity of ≤ 9.5 U/g Hb and one sample had normal enzyme activity. All 38 intermediate samples were from females. Of these, 21 had G6PD activity of between 20% and 60%, and 17 samples showed normal G6PD activity. Twenty-seven of the 38 samples were available for mutation analysis of which 13 had normal G6PD activity. Eleven of the 13 samples with normal G6PD activity had identifiable G6PD mutations. Glucose-6-phosphate dehydrogenase heterozygote females cannot be identified by FST if fluorescence is reported as absent or present. Distinguishing samples with intermediate fluorescence from absent and bright fluorescence improves detection of heterozygote females with mild G6PD deficiency. Mutational studies confirmed that 85% of intermediate samples with normal enzyme activity had identifiable G6PD mutations.

The effect of different haemoglobins on the glucose-6-phosphate dehydrogenase deficiency screening test (Brewer's test)

Glucose-6-phosphate dehydrogenase (G6PD) deficiency and haemoglobinopathies are common causes of haemolytic anaemia in Sri Lanka. Even though G6PD enzyme assay is indicated for diagnosis of G6PD deficiency, due to lack of reagents many of the government hospitals in Sri Lanka make the diagnosis only on the basis of a screening test (Brewer's test) for this deficiency. Both these tests are indicated in patients with chronic haemolytic anaemia. The aim of the study was to observe the effect of different haemoglobins on screening test for G6PD deficiency. We investigated the patients and carriers for commoner haemoglobinopathies (Hb E, Hb S, and Hb D) and thalassaemias using G6PD deficiency screening test as well as G6PD enzyme assay. The results show that patients with Hb E/β thalassaemia, Hb E trait and Hb E disease gave a false positive reaction with G6PD screening test (n=47), even though their G6PD enzyme levels were normal. Two subjects with Hb E showed low enzyme levels with positive screening test. Hb S (n=5) and Hb D (n=2) did not have any effect on the screening test for G6PD deficiency. The patients with Hb E and normal enzyme levels are likely to be misdiagnosed as having G6PD deficiency, if only the screening test is utilized. This study emphasizes the necessity for employing an enzyme assay method for the diagnosis of G6PD deficiency, at least in districts with high Hb E prevalence. Keywords: G6PD; Brewer's test; thalassaemia; haemoglobinopathy. DOI: 10.4038/jdp.v5i1.2957 Journal of Diagnostic Pathology 2006/07; 5: 30-34

Evaluation of a Rapid Qualitative Enzyme Chromatographic Test for Glucose-6-Phosphate Dehydrogenase Deficiency

Rapid determination of glucose-6-phosphate dehydrogenase (G6PD) status is desirable when it is necessary to use a drug contraindicated in G6PD-deficient persons, such as use of primaquine for malaria prevention or treatment. The purpose of this study was to compare a new, rapid, qualitative enzyme chromatographic test for deficiency of G6PD to a standard reference method. Samples from 196 G6PD-normal persons and 50 G6PD-deficient persons were evaluated. The sensitivity of the experimental rapid test was 0.98 and the specificity was 0.98 using specimens preserved in heparin, and 0.98 and 0.97, respectively, for specimens preserved in EDTA. Positive and negative predictive values were 0.72 and 1.00, respectively, for the test for heparinized specimens and 0.65 and 1.00, respectively, for the EDTA-preserved samples. This rapid test for G6PD deficiency is a sensitive method for screening of G6PD deficiency that requires minimal training and equipment and enables rapid identification of G6PD-deficient persons.

Primary HIV infection presenting as haemolytic crisis in a patient with previously undiagnosed glucose 6-phosphate dehydrogenase deficiency

Primary HIV infection presenting as haemolytic crisis in a patient with previously undiagnosed glucose 6-phosphate dehydrogenase deficiency

Neonatal Hyperbilirubinemia: Don't Let Glucose-6-phosphate Dehydrogenase Deficiency off the Hook: In Reply

We agree with Kaplan and Hammerman: there is substantial evidence that glucose-6-phosphate dehydrogenase (G6PD) deficiency is associated with neonatal hyperbilirubinemia.1–4 And, our results do not contest that association. Rather, our findings raise questions about the utility of a particular DNA-based G6PD screening test5 as a predictor of neonatal hyperbilirubinemia. As we pointed out in our article,6 there are several reasons why a positive G6PD mutation analysis did not correlate with hyperbilirubinemia in our study sample: (1) some mutations may not result in inadequate G6PD enzyme levels; (2) some mutations may result in low enzyme activity levels but not hyperbilirubinemia; and (3) some mutations that result in low enzyme activity and hyperbilirubinemia may not be detected by this screening test.Studies are needed to further evaluate the predictive accuracy of and relationship between alternative methods of G6PD-deficiency screening. Infants enrolled onto these studies should have the following tests performed: G6PD mutation analysis, G6PD enzyme level, UDPGT1 polymorphism analysis, and daily bilirubin levels. Investigators can then compare the predictive value of alternative screening tests for G6PD deficiency, determine reasons for divergent screening test results, and evaluate the contribution of glucuronidation defects to hyperbilirubinemia. Even more important is that these studies can inform us about the incremental predictive value of G6PD screening tests above and beyond the predictive information provided by the predischarge bilirubin level (expressed as a risk zone on the hour-specific bilirubin nomogram) and the infant's gestational age, the 2 factors shown to be most predictive of significant hyperbilirubinemia.

Attitudes and beliefs of pediatricians and genetic counselors regarding testing and screening for CF and G6PD: Implications for policy

There is wide variability in conditions included in state newborn screening (NBS) panels. The American College of Medical Genetics (ACMG) was commissioned by Health Resources and Services Administration to develop a uniform NBS panel. Based on survey data, the ACMG committee proposed a panel that included cystic fibrosis (CF) and glucose-6-phosphate dehydrogenase deficiency (G6PD), although G6PD was excluded from their final recommendations. We examine the attitudes of pediatricians and genetic counselors concerning screening for these two conditions. Data were collected as part of two different studies. Koopmans and Ross surveyed a random sample of 600 pediatricians from four states based on their NBS panels. Hiraki et al. surveyed genetic counselors who were members of the National Society of Genetic Counselors (NSGC) listserv. For this analysis, we compare the health care professionals' (HCPs') attitudes toward a universal NBS program for CF and G6PD, and how their support is influenced by state policy and personal interest in testing their own children. Two hundred twenty-three pediatricians and 267 genetic counselors provided partial or complete responses. Pediatricians are more likely to support NBS for both CF (84%) and G6PD (58%) than genetic counselors (56%, P < 0.001 and 39%, P < 0.001, respectively). Both pediatricians and genetic counselors' attitudes toward screening correlate with interest in screening their own children (P < 0.001). Interest in CF screening also correlates with state policy (pediatricians, P < 0.001; genetic counselors, P < 0.025). The correlation of professional recommendations with state policies and personal preferences reinforces the need for systematic evidence-based reviews rather than reliance on stakeholder opinions for developing national guidelines.